JP2014058494A - Tear stain or slaver stain inhibitor - Google Patents
Tear stain or slaver stain inhibitor Download PDFInfo
- Publication number
- JP2014058494A JP2014058494A JP2012246573A JP2012246573A JP2014058494A JP 2014058494 A JP2014058494 A JP 2014058494A JP 2012246573 A JP2012246573 A JP 2012246573A JP 2012246573 A JP2012246573 A JP 2012246573A JP 2014058494 A JP2014058494 A JP 2014058494A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- tears
- tear
- chelate compound
- stain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
Description
本発明は、新規な涙やけまたはヨダレやけの抑制剤に関する。 TECHNICAL FIELD The present invention relates to a novel tear and / or drooling inhibitor.
涙やけは、動物の内眼角の被毛および皮膚が涙によって茶色に染色される症状を呈することをいい、睫毛の刺激、眼瞼の形態異常、アレルギーなどにより発症する流涙症に伴う症状の1つとして知られている。流涙症では、継続的に溢れた涙が目頭を汚すため、眼から鼻にかけて涙やけ特有の茶色の跡が生じてしまう（非特許文献１、非特許文献２）。また、ヨダレやけは、涙やけと同様、動物の被毛および皮膚が涙によって茶色に染色される症状を特徴としている。このような症状は、白色犬種、特にはトイ犬種やミニチュア犬種で多く見られる症状であり（非特許文献３）、最近ではその改善を願う飼い主の数も増加してきている。 Tears and burns refer to symptoms such as the hair of the inner horn of an animal and the skin being stained brown by tears. It is one of the symptoms associated with lacrimation caused by irritation of eyelashes, abnormal eyelid morphology, allergies, etc. Known as one. In lacrimation, tears overflowing continuously stains the head of the eyes, resulting in a brown mark peculiar to tearing from the eyes to the nose (Non-patent Documents 1 and 2). In addition, similar to tears and tears, yodare burns are characterized by the condition that animal hair and skin are stained brown by tears. Such a symptom is a symptom frequently seen in white dog breeds, particularly toy breeds and miniature breeds (Non-patent Document 3), and recently, the number of owners who wish to improve the breed has also increased.
近年、涙やけまたはヨダレよけのメカニズムについて研究が進められている。
例えば、涙液中のラクトフェリンは涙やけ発症の原因であることが報告されている（非特許文献４）。また、ラクトフェリンの赤色発色には、ラクトフェリン−鉄イオン錯体が寄与することが報告されている（非特許文献５、特許文献１）。
In recent years, research has been carried out on the mechanism of tears and rids.
For example, it has been reported that lactoferrin in tears is the cause of tears (Non-Patent Document 4). Moreover, it has been reported that the lactoferrin-iron ion complex contributes to the red color development of lactoferrin (Non-patent Document 5, Patent Document 1).
また、非特許文献６には、被毛哺乳動物の唾液中に、涙液と同様、被毛および皮膚の着色の原因となるラクトフェリンが含有されていることが報告されている。 Further, Non-Patent Document 6 reports that lactoferrin, which causes coloring of hair and skin, is contained in saliva of haired mammals as well as tears.
一方、特許文献２には、広範なＮ−（６，８−ジメルカプトオクタノイル）基を有する金属キレート化合物が、メラニン除去剤として用いうることが記載されている。しかしながら、特許文献２には、上記金属キレート化合物の涙やけまたはヨダレやけ抑制効果は何ら記載されていない。 On the other hand, Patent Document 2 describes that metal chelate compounds having a wide range of N- (6,8-dimercaptooctanoyl) groups can be used as melanin removal agents. However, Patent Document 2 does not describe any effect of the above-described metal chelate compound to suppress tearing or burning.
このように、涙やけまたはヨダレやけに対する有効な処置方法は未だに十分に確立されておらず、効果的な涙やけまたはヨダレやけの抑制手段が依然として求められている。 Thus, an effective treatment method for tears and / or drowning has not been sufficiently established, and there is still a need for an effective means for suppressing tears and / or dripping.
本発明者らは、今般、Ｎ−（６，８−ジメルカプトオクタノイル）基を有する特定の金属キレート化合物が、非ヒト哺乳動物の涙やけまたはヨダレよけを効果的に抑制しうることを見出した。本発明は、かかる知見に基づくものである。 The present inventors have now confirmed that a specific metal chelate compound having an N- (6,8-dimercaptooctanoyl) group can effectively suppress tearing or drooling prevention in non-human mammals. I found it. The present invention is based on such knowledge.
したがって、本発明は、新規な非ヒト哺乳動物の涙やけまたはヨダレやけの抑制剤を提供することをその目的とする。 Accordingly, an object of the present invention is to provide a novel non-human mammal tear or drooling inhibitor.
本発明には、以下の発明が包含される。
（１）下式（Ｉ）で表される金属キレート化合物またはその薬理学上許容可能な塩を含有する、非ヒト哺乳動物の涙やけまたは涙やけの抑制剤：
（２）Ｎ−結合のアミノ酸がヒスチジンである、（１）に記載の抑制剤。
（３）Ｎ−結合のアミノＣ１〜Ｃ７アルキルスルホン酸が、アミノエチルスルホン酸である、（１）または（２）に記載の抑制剤。
（４）非ヒト哺乳動物が、イヌ科動物またはネコ科動物である、（１）〜（３）のいずれかに記載の抑制剤。
The present invention includes the following inventions.
(1) An inhibitor of tears or tears in a non-human mammal containing a metal chelate compound represented by the following formula (I) or a pharmacologically acceptable salt thereof:
(2) The inhibitor according to (1), wherein the N-linked amino acid is histidine.
(3) The inhibitor according to (1) or (2), wherein the N-linked amino C1-C7 alkylsulfonic acid is aminoethylsulfonic acid.
(4) The inhibitor according to any one of (1) to (3), wherein the non-human mammal is a canine or feline.
本発明によれば、非ヒト哺乳動物の涙やけまたはヨダレよけを効果的に治療または予防することができる。 According to the present invention, it is possible to effectively treat or prevent tears or drooling prevention in non-human mammals.
本発明の涙やけまたはヨダレよけの抑制剤は、Ｎ−（６，８−ジメルカプトオクタノイル）基を有する式（I）の金属キレート化合物を有効成分として含有することを一つの特徴としている。かかる金属キレート化合物が、涙やけまたはヨダレよけに対する顕著な抑制作用を有することは意外な事実である。 One feature of the present invention is an agent for preventing tears or drooling, which contains, as an active ingredient, a metal chelate compound of formula (I) having an N- (6,8-dimercaptooctanoyl) group. . It is a surprising fact that such a metal chelate compound has a remarkable inhibitory action against tears or drooling.
式（I）におけるＮ−結合のアミノ酸は、同一分子内にカルボキシル基とアミノ酸を有する、α−アミノ酸およびβ−、γ−、δ−、ε−アミノ酸などのω−アミノ酸、並びにアミノメチルシクロヘキサンカルボン酸、アントラニル酸およびアントラニル酸エチルなどの特殊アミノ酸をいう。α−アミノ酸としては、たとえばグリシン、アラニン、バリン、ロイシン、イソロイシン、セリン、トレオニン、チロシン、システイン、メチオニン、アスパラギン酸、アスパラギン、グルタミン酸、グルタミン、アルギニン、リジン、ヒスチジン、フェニルアラニン、トリプトファンなどが挙げられ、β−アミノ酸としてはβ−アラニンが挙げられ、γ−アミノ酸としてはγ−アミノ−ｎ−酪酸（ＧＡＢＡ）やカルニチンが挙げられ、δ−アミノ酸としては５−アミノレブリン酸や５−アミノ吉草酸、ε−アミノ酸としては６−アミノヘキサン酸が挙げられる。これらアミノ酸のうち、ヒスチジンが特に好ましい。 The N-linked amino acids in the formula (I) include α-amino acids and ω-amino acids such as β-, γ-, δ-, and ε-amino acids, and aminomethylcyclohexanecarboxyl having a carboxyl group and an amino acid in the same molecule. Special amino acids such as acids, anthranilic acid and ethyl anthranilate. Examples of α-amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, tyrosine, cysteine, methionine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, lysine, histidine, phenylalanine, tryptophan, and the like. Examples of β-amino acids include β-alanine, examples of γ-amino acids include γ-amino-n-butyric acid (GABA) and carnitine, examples of δ-amino acids include 5-aminolevulinic acid, 5-aminovaleric acid, and ε -Amino acid includes 6-aminohexanoic acid. Of these amino acids, histidine is particularly preferred.
式（I）におけるＮ−結合のアミノＣ１〜Ｃ７アルキルスルホン酸におけるアルキルは、鎖状であっても分岐状であっても環状であってもよい。上記アミノＣ１〜Ｃ７アルキルスルホン酸の具体例としては、特に限定されないが、好ましくは同一分子内にスルホン酸基とアミノ酸を有するアミノエタンスルホン酸（タウリン）である。 The alkyl in the N-linked amino C1-C7 alkyl sulfonic acid in formula (I) may be linear, branched or cyclic. Although it does not specifically limit as a specific example of the said amino C1-C7 alkylsulfonic acid, Preferably it is aminoethanesulfonic acid (taurine) which has a sulfonic acid group and an amino acid in the same molecule.
式（Ｉ）の金属キレート化合物の金属は、亜鉛であることが好ましい。しかしながら、上記金属は、涙やけまたはヨダレやけを抑制しかつ式（I）のキレートを形成しうる限り他の金属であってもよい。 The metal of the metal chelate compound of formula (I) is preferably zinc. However, the metal may be other metals as long as they can suppress tearing or dripping and form a chelate of formula (I).
本化合物の薬学的に許容可能な塩としては、特に限定されず、ナトリウム塩やカリウム塩などのアルカリ金属塩およびカルシウム塩やマグネシウム塩などのアルカリ土類金属塩が挙げられるが、好ましくはナトリウム塩である。 The pharmaceutically acceptable salt of the present compound is not particularly limited, and includes alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt, preferably sodium salt. It is.
本発明の好ましい態様によれば、式（Ｉ）で表される金属キレート化合物またはその薬理学上許容可能な塩は、Ｎ−（６，８−ジメルカプトオクタノイル）ヒスチジンナトリウム・亜鉛キレート化合物およびＮ−（６，８−ジメルカプトオクタノイル）アミノエタンスルホン酸ナトリウム・亜鉛キレート化合物から選択されるものである。 According to a preferred embodiment of the present invention, the metal chelate compound represented by formula (I) or a pharmacologically acceptable salt thereof is N- (6,8-dimercaptooctanoyl) histidine sodium / zinc chelate compound and N- (6,8-dimercaptooctanoyl) aminoethanesulfonic acid sodium / zinc chelate compound.
本発明の式（I）の金属キレート化合物は、ＷＯ２００４／０２４１３９号公報（特許文献２）に記載の方法に従い合成することができる。製造方法の一例としては、α−リポ酸をクロロホルムまたはアセトニトリルに溶かし、トリエチルアミン存在下、クロル炭酸エチルを用いて混合酸無水物法によりアミンアルキルスルホン酸またはアミノ酸を各々、カップリングさせ、Ｎ−（６，８−ジメルカプトオクタノイル）基を有する式（I）の化合物を得る。これらを亜鉛と酢酸（または塩酸）で還元して、各々、目的の化合物を得ることができる。さらに、当該化合物を、例えばアルカリ塩に導く場合は、その遊離酸を水に溶解または懸濁して置き、水酸化アルカリで中和して溶かした後、濃縮し、アルコールを加えて析出する結晶を濾取すれば高収率で目的化合物の塩を得ることができる。 The metal chelate compound of the formula (I) of the present invention can be synthesized according to the method described in WO 2004/024139 (Patent Document 2). As an example of the production method, α-lipoic acid is dissolved in chloroform or acetonitrile, and in the presence of triethylamine, amine alkylsulfonic acid or amino acid is coupled by mixed acid anhydride method using ethyl chlorocarbonate, and N- ( A compound of formula (I) having a 6,8-dimercaptooctanoyl) group is obtained. These can be reduced with zinc and acetic acid (or hydrochloric acid) to give the desired compounds, respectively. Furthermore, when the compound is converted into an alkali salt, for example, the free acid is dissolved or suspended in water, neutralized with an alkali hydroxide, dissolved, concentrated, added with alcohol to precipitate crystals. By filtering, the salt of the target compound can be obtained in high yield.
本発明の涙やけまたはヨダレやけの抑制剤は、式（Ｉ）で表される金属キレート化合物をそのまま適用してもよく、他の薬学上許容可能な添加剤とともに製剤の形態としてもよい。したがって、本発明の涙やけまたはヨダレやけ抑制剤における式（Ｉ）で表される金属キレート化合物の含有量は、特に限定されないが、例えば、０．０５〜１００重量％とすることができる。 The metal chelate compound represented by formula (I) may be applied as it is to the tear or scorching agent of the present invention, or it may be in the form of a preparation together with other pharmaceutically acceptable additives. Accordingly, the content of the metal chelate compound represented by the formula (I) in the tear or scorch inhibitor of the present invention is not particularly limited, but may be, for example, 0.05 to 100% by weight.
本発明の涙やけまたはヨダレやけの抑制剤の剤形は、特に限定されないが、例えば、点眼剤、スプレー剤、貼付剤、外用液剤(リニメント剤、ローション剤)、軟膏剤、クリーム剤、ゲル剤等が挙げられる。また、本発明では、上記いずれかの剤形を組み合わせて用いてもよい。具体的には、例えば、本発明の涙やけまたはヨダレやけの抑制剤は、ローション剤とクリーム剤とを組み合わせたキットとして提供することもでき、本発明にはかかる態様も包含される。 The dosage form of the present invention is not particularly limited, and includes, for example, eye drops, sprays, patches, external liquids (liniments, lotions), ointments, creams, gels. Etc. In the present invention, any of the above dosage forms may be used in combination. Specifically, for example, the tear or scorching agent of the present invention can be provided as a kit combining a lotion and a cream, and the present invention includes such an embodiment.
また、涙やけまたはヨダレやけの抑制剤に含有される薬学上許容可能な添加剤としては、特に限定されないが、精製水等の水性媒体、安定剤、保存剤、酸化防止剤、調整剤、紫外線吸収剤、紫外線散乱剤、キレート剤、抗菌剤等が挙げられる。また、涙やけまたはヨダレやけの抑制剤をイヌ用点眼薬とする場合には、例えば、硫酸亜鉛やホウ酸など、通常のイヌ用目薬に含まれている他の成分を適宜溶含有させてもよい。 In addition, the pharmaceutically acceptable additive contained in the tear or scorching agent is not particularly limited, but it is not limited to an aqueous medium such as purified water, a stabilizer, a preservative, an antioxidant, a regulator, an ultraviolet ray. Examples include absorbents, ultraviolet light scattering agents, chelating agents, and antibacterial agents. In addition, in the case of using an eye drop for dogs as an inhibitor of tears or scorching or dripping, for example, other components contained in normal eye drops such as zinc sulfate and boric acid may be appropriately dissolved. Good.
本発明の涙やけまたはヨダレやけの抑制剤は、例えば、式（Ｉ）で表される金属キレート化合物と、上記成分とを公知手法により混合することにより製造することができる。例えば、式（Ｉ）で表される金属キレート化合物と、上記成分を適量の精製水に溶解させることによって製造してもよい。 The tear or scorch inhibitor of the present invention can be produced, for example, by mixing the metal chelate compound represented by the formula (I) and the above components by a known method. For example, it may be produced by dissolving the metal chelate compound represented by the formula (I) and the above components in an appropriate amount of purified water.
また、本発明の式（Ｉ）で表される金属キレート化合物によれば、非ヒト哺乳動物の涙やけまたはヨダレを抑制し、ひいてはその治療または予防することができる。したがって、本発明の好ましい態様によれば、本発明の式（Ｉ）で表される金属キレート化合物の有効量を、それを必要とする非ヒト哺乳動物に投与することを含んでなる、非ヒト哺乳動物の涙やけまたはヨダレの抑制方法が提供される。また、本発明のより好ましい態様によれば、上記抑制は、治療または予防を含んでなる。また、本発明の別の態様によれば、非ヒト哺乳動物の涙やけまたはヨダレやけの抑制剤の製造における、式（Ｉ）で表される金属キレート化合物の使用が提供される。また、本発明の別の好ましい態様によれば、涙やけまたはヨダレやけの抑制剤は、涙やけの治療または予防に用いられる。 Moreover, according to the metal chelate compound represented by the formula (I) of the present invention, it is possible to suppress tearing or drooling in a non-human mammal, and to treat or prevent it. Thus, according to a preferred embodiment of the present invention, a non-human comprising comprising administering an effective amount of the metal chelate compound represented by formula (I) of the present invention to a non-human mammal in need thereof. Methods of suppressing tears or drooling in mammals are provided. Moreover, according to a more preferred embodiment of the present invention, the suppression comprises treatment or prevention. Moreover, according to another aspect of the present invention, there is provided use of the metal chelate compound represented by formula (I) in the manufacture of an inhibitor of tears or drooling in non-human mammals. Moreover, according to another preferable aspect of the present invention, the tear or scorching agent is used for treating or preventing tears.
式（Ｉ）の金属キレート化合物の投与方法は、涙やけの対象となる毛または皮膚に適用しうる限り特に限定されず、例えば、所望の剤形に調製された金属キレート化合物を、点眼、拭き取り（清拭など）、スプレーまたは貼付などの処置により対象部位に適用することができる。 The administration method of the metal chelate compound of the formula (I) is not particularly limited as long as it can be applied to the hair or skin to be burned. For example, the metal chelate compound prepared in a desired dosage form is instilled, wiped off (Wiping etc.), can be applied to the target site by spraying or sticking.
式（Ｉ）の金属キレート化合物の有効量は、特に限定されず、適用される動物の種類、大きさ、性別等に応じて当業者が適宜設定することができ、例えば、約０．０１mg/mL以上、好ましくは約０．０５mg/mL以上の溶液１〜数mLを、1日１回〜1日数回で適用してもよい。 The effective amount of the metal chelate compound of the formula (I) is not particularly limited, and can be appropriately set by those skilled in the art according to the kind, size, sex, etc. of the applied animal. One to several mL of a solution of mL or more, preferably about 0.05 mg / mL or more may be applied once a day to several times a day.
また、本発明の非ヒト哺乳動物は、限定されないが、好ましくは、被毛哺乳動物であり、より好ましくはイヌ科動物、ネコ科動物またはウザギ科動物、
であり、さらに好ましくイヌ科動物またはネコ科動物であり、さらに一層好ましくはイヌまたはネコである。
In addition, the non-human mammal of the present invention is not limited, but is preferably a haired mammal, more preferably a canine, feline, or rabbit animal,
More preferably a canine or feline, and still more preferably a dog or a cat.
以下、本発明を実施例によって説明するが、本発明はこれら実施例に限定されない。なお、以下の実験において、ラット(LEW/SsNSls, ♀, 5週齢, 90〜140g)は日本エスエルシー株式会社から購入した。また、ラクトフェリン(牛乳由来)、および鉄粉末(45μm, 99.9%)は和光純薬工業株式会社から購入した。また、Ｎ−（６，８−ジメルカプトオクタノイル）ヒスチジンナトリウム・亜鉛キレート化合物(DHL-His-Zn)およびＮ−（６，８−ジメルカプトオクタノイル）アミノエタンスルホン酸ナトリウム・亜鉛キレート化合物(DHL-Tau-Zn)はＷＯ２００４／０２４１３９号公報に記載の方法に基づいて製造し、試験に用いた。また、水はMilli-Q超純水製造装置(日本ミリポア株式会社)から採水して使用した。 EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these Examples. In the following experiment, rats (LEW / SsNSls, rabbit, 5 weeks old, 90-140 g) were purchased from Japan SLC Co., Ltd. Lactoferrin (derived from milk) and iron powder (45 μm, 99.9%) were purchased from Wako Pure Chemical Industries, Ltd. Further, N- (6,8-dimercaptooctanoyl) histidine sodium / zinc chelate compound (DHL-His-Zn) and N- (6,8-dimercaptooctanoyl) aminoethanesulfonic acid sodium / zinc chelate compound ( DHL-Tau-Zn) was produced based on the method described in WO 2004/024139 and used for testing. Water was collected from Milli-Q ultrapure water production equipment (Nippon Millipore Corporation) and used.
試験例１：鉄粉末を添加したラクトフェリン水溶液の変色の確認
水1 mLからなるサンプルNo.１、ラクトフェリン約3mgおよび水1 mL混合したサンプルNo.２、鉄粉末約7mgおよび水1 mL混合したサンプルNo.３、ならびに、ラクトフェリン約3mg、鉄粉末約7mgおよび水1 mL混合したサンプルNo.４をそれぞれ調製した。次に、これらのサンプルを室温下で1週間静置し、色の変化を観察した。
なお、色の変化は、専門パネル3名により以下の基準に従って評価した。
Test Example 1: Confirmation of discoloration of lactoferrin aqueous solution added with iron powder Sample No. 1 consisting of 1 mL of water, sample No. 2 mixed with about 3 mg of lactoferrin and 1 mL of water, sample mixed with about 7 mg of iron powder and 1 mL of water No. 3 and sample No. 4 in which about 3 mg of lactoferrin, about 7 mg of iron powder and 1 mL of water were mixed were prepared. Next, these samples were allowed to stand at room temperature for 1 week, and the color change was observed.
The color change was evaluated according to the following criteria by three specialist panels.
着色（目視による外観評価）
５ 全く着色は感じられない（溶液に透明感を感じる）
４ 着色は感じられない
３ わずかに着色が感じられる
２ 着色が感じられる
１ 強く着色が感じられる
Coloring (visual appearance evaluation)
5 No color at all (feels transparent in the solution)
4 Coloring is not felt 3 Slight coloring is felt 2 Coloring is felt 1 Strong coloring is felt
その結果は表１に示される通りであった。
サンプルNo.１〜３では、着色が確認されなかった。一方で、ラクトフェリンおよび鉄粉末を含有するサンプルNo.4では、赤褐色の着色が明確に確認された。 In samples No. 1 to 3, coloring was not confirmed. On the other hand, in sample No. 4 containing lactoferrin and iron powder, reddish brown coloring was clearly confirmed.
試験例２：ラット体毛変色の確認
ラクトフェリンおよび鉄による涙やけの検討１
試験例１に記載した組成で調製した溶液(サンプルNo.4)を1週間室温で静置し溶液の着色を確認した。次に、この溶液に刈り取ったラットの体毛を浸し3ヶ月室温下で静置した。その3ヶ月後、ラットの体毛を溶液から取り出し、ろ紙上に置き、付着物が確認できなくなるまで水で洗浄した。次に、室温下で乾燥させ、体毛の染色状況を観察した。
Test Example 2: Confirmation of discoloration of rat hair
Examination of tears caused by lactoferrin and iron 1
A solution (sample No. 4) prepared with the composition described in Test Example 1 was allowed to stand at room temperature for 1 week, and the color of the solution was confirmed. Next, the rat's body hair cut into this solution was immersed and allowed to stand at room temperature for 3 months. Three months later, the rat's hair was removed from the solution, placed on filter paper, and washed with water until no deposits could be confirmed. Next, it was dried at room temperature, and the dyeing state of body hair was observed.
その結果は図１に示される通りであった。
白色だったラットの体毛は、薄い褐色に染色された。この着色は白色体毛を有する哺乳動物に見られる涙やけの着色と同様であった。このように、ラクトフェリンと鉄を含有する着色溶液によってラット体毛が染色されたことから、鉄イオンと結合したラクトフェリンが涙やけの原因の1つであることが確認された。
The result was as shown in FIG.
The rat hair, which was white, was stained light brown. This coloring was similar to the tearing color seen in mammals with white hair. Thus, since rat hair was stained with a colored solution containing lactoferrin and iron, it was confirmed that lactoferrin bound to iron ions was one of the causes of tears.
試験例３：白色犬の体毛変色の確認
ラクトフェリンおよび鉄による涙やけの検討２
白色犬の体毛を用いる以外、試験例２と同様の手法により試験を行い、体毛染色状況を観察した。
Test Example 3: Confirmation of discoloration of white dog body hair
Examination of tears caused by lactoferrin and iron 2
A test was performed in the same manner as in Test Example 2 except that white dog body hair was used, and the body hair staining situation was observed.
その結果は図２に示される通りであった。
白色だったイヌの体毛は、薄い褐色に染色された。この着色は涙やけの着色と同様であった。このように、ラクトフェリンと鉄を含有する着色溶液によってイヌの体毛が染色されたことから、鉄イオンと結合したラクトフェリンが涙やけの原因の1つであることが確認された。
The result was as shown in FIG.
White dog hair was stained light brown. This coloring was similar to that of tears. Thus, since the hair of dogs was stained with a coloring solution containing lactoferrin and iron, it was confirmed that lactoferrin bound to iron ions was one of the causes of tears.
試験例４：Ｎ−（６，８−ジメルカプトオクタノイル）ヒスチジンナトリウム・亜鉛キレート化合物（DHL-His-Zn）添加による変色抑制効果の確認
ラクトフェリン約3mgおよび鉄粉末約7mgを含有する溶液中DHL-His-Zn濃度が0.055mg/mL〜2.21mg/mLであるサンプルNo.5〜9を調製し、１週間静置した。次に、得られた溶液の着色状態を観察し、試験例１と同様の手法により着色評価を行った。
Test Example 4: Confirmation of discoloration suppression effect by adding N- (6,8-dimercaptooctanoyl) histidine sodium / zinc chelate compound (DHL-His-Zn) DHL in a solution containing about 3 mg of lactoferrin and about 7 mg of iron powder Sample Nos. 5 to 9 having -His-Zn concentrations of 0.055 mg / mL to 2.21 mg / mL were prepared and allowed to stand for 1 week. Next, the coloring state of the obtained solution was observed, and coloring evaluation was performed by the same method as in Test Example 1.
その結果は、表２に示される通りであった。
溶液中のDHL-His-Zn濃度が増加するに従い、薄い橙色から透明に変化していた。また、DHL-His-Zn濃度0.55mg/mL以上のサンプルNo.7〜9では着色が生じず、溶液は無色透明であった。すなわち、DHL-His-Znによりラクトフェリンによる着色を用量依存的に抑制できることが確認された。この結果から、DHL-His-Znを含有した溶液を眼周辺に適用することにより、ラクトフェリンによる体毛の染色を抑制し、涙やけを予防しうることが示唆される。 As the DHL-His-Zn concentration in the solution increased, it changed from light orange to transparent. In Sample Nos. 7 to 9 having a DHL-His-Zn concentration of 0.55 mg / mL or more, coloring did not occur, and the solution was colorless and transparent. That is, it was confirmed that coloring by lactoferrin can be suppressed in a dose-dependent manner by DHL-His-Zn. From this result, it is suggested that by applying a solution containing DHL-His-Zn to the periphery of the eye, staining of body hair by lactoferrin can be suppressed and tearing can be prevented.
試験例５：Ｎ−（６，８−ジメルカプトオクタノイル）アミノエタンスルホン酸ナトリウム・亜鉛キレート化合物（DHL-Tau- Zn）添加による変色抑制効果の確認
ラクトフェリン約3mgおよび鉄粉末約7mgを含有する溶液中DHL-Tau- Zn濃度が３．９mg/mlであるサンプルNo.10を調製し、１週間静置した。次に、得られた溶液の着色状態を観察し、試験例１と同様の手法によりサンプルNo.4（コントロールとの比較により着色評価を行った。
Test Example 5: Confirmation of discoloration inhibiting effect by adding sodium N- (6,8-dimercaptooctanoyl) aminoethanesulfonate / zinc chelate compound (DHL-Tau-Zn) Containing about 3 mg of lactoferrin and about 7 mg of iron powder Sample No. 10 having a DHL-Tau-Zn concentration in the solution of 3.9 mg / ml was prepared and allowed to stand for 1 week. Next, the colored state of the obtained solution was observed, and coloring evaluation was performed by comparing the sample No. 4 (comparison with the control) in the same manner as in Test Example 1.
その結果は、表３に示される通りであった。
試験例３のDHL-His-Znと同様にＮ−（６，８−ジメルカプトオクタノイル）アミノ化合物亜鉛コンプレクスであるDHL-Tau-Znを用いた結果、ラクトフェリンによる着色を抑制できることが確認された。 Similar to DHL-His-Zn in Test Example 3, as a result of using DHL-Tau-Zn which is an N- (6,8-dimercaptooctanoyl) amino compound zinc complex, it was confirmed that coloring by lactoferrin can be suppressed. .
試験例６：市販品の涙やけ抑制剤の添加による変色抑制効果の確認
ラクトフェリン約3mgおよび鉄粉末約7mgを含有する溶液中市販品の涙やけ抑制剤１mlを添加したサンプルNo.11〜13を調製し、１週間静置した。次に、得られた溶液の着色状態を観察し、試験例１と同様の手法によりサンプルNo.4（コントロールとの比較により着色評価を行った。
なお、市販品は、サンプルNo.11は涙やけイヤー（商標）（トーラス株式会社）、サンプルNo.12はワンレイ 涙やけクリーナー（商標）（牧産業株式会社）およびサンプルNo.13はEye Envy（商標）NR（Eye envy社）を用いた。
Test Example 6: Confirmation of Discoloration Suppressing Effect by Addition of Commercially Available Tear Burn Inhibitor Sample Nos. 11 to 13 to which 1 ml of a commercially available tear inhibitor in a solution containing about 3 mg of lactoferrin and about 7 mg of iron powder were added Prepared and allowed to stand for 1 week. Next, the colored state of the obtained solution was observed, and coloring evaluation was performed by comparing the sample No. 4 (comparison with the control) in the same manner as in Test Example 1.
Sample No. 11 is tear tears (trademark) (Torus Co., Ltd.), sample No. 12 is One Ray tear tear cleaner (trademark) (Maki Sangyo Co., Ltd.), and sample No. 13 is Eye Envy (trades). (Trademark) NR (Eye envy) was used.
その結果は、表４に示される通りであった。
市販品の評価スコアは、試験例３および４におけるDHL-His-Zn（スコア５） およびDHL-Tau- Zn（スコア３）と比較して、低かった。 The evaluation score of the commercial product was low compared with DHL-His-Zn (score 5) and DHL-Tau-Zn (score 3) in Test Examples 3 and 4.
試験例７：涙やけ抑制効果のインビボ確認試験
DHL-His-Znを含有するローション剤（DHL-His-Zn 0.1重量%含有、溶媒−水）と、DHL-His-Znを含有するクリーム剤（DHL-His-Zn 0.5重量%含有、基剤−ポリアクリルアミド）を用意した。次に、涙やけを有するイヌ（犬種：MIX(マルチーズとプードル)、年齢5ヶ月、メス）の変色した毛に、少なくとも１日２回ローション剤およびクリーム剤を塗布することを４週間継続した。
Test Example 7: In vivo confirmation test of the effect of suppressing tearing
DHL-His-Zn containing lotion (DHL-His-Zn 0.1wt%, solvent-water) and DHL-His-Zn containing cream (DHL-His-Zn 0.5wt%, base) -Polyacrylamide) was prepared. Next, applying lotion and cream to the discolored hair of dogs with tears (dog breed: MIX (Maltes and Poodle), age 5 months, female) at least twice a day for 4 weeks. .
その結果を、図３の写真に示す。
試験前（Ａ）では目の周りの毛は着色しているのに対して、試験後（Ｂ）では目の周りの着色はほぼ消失していた。
The result is shown in the photograph of FIG.
Before the test (A), the hair around the eyes was colored, whereas after the test (B), the coloring around the eyes was almost lost.
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